Hydantoin hydroxamic acid type selective inhibitor for histone deacetylase 6 subtype and preparation method and applications thereof

A technology of hydantoin hydroxime and sirtuin, which is applied in the field of medicine and can solve the problems of limiting the clinical application of HDAC inhibitors, toxic and side effects, etc.

Active Publication Date: 2019-08-20
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although HDAC inhibitors such as SAHA and LBH-589 have achieved certain results in cancer treatment, the HDAC inhibitors currently on the market are all pan-inhibitors, and have inhibitory effects on different subtypes of HDAC. The indiscriminate inhibition of HDAC leads to a series of toxic and side effects, such as SAHA is often accompanied by a series of side effects such as diarrhea, fatigue, and leukopenia in clinical practice, which greatly limits the clinical application of HDAC inhibitors

Method used

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  • Hydantoin hydroxamic acid type selective inhibitor for histone deacetylase 6 subtype and preparation method and applications thereof
  • Hydantoin hydroxamic acid type selective inhibitor for histone deacetylase 6 subtype and preparation method and applications thereof
  • Hydantoin hydroxamic acid type selective inhibitor for histone deacetylase 6 subtype and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0132] Example 1. Synthesis of ((4-chlorophenyl) carbamoyl) glutamic acid (5)

[0133] Dissolve p-chloroaniline (10.2g, 80mmol) in dichloromethane (150mL), slowly drop it into a solution of triphosgene (8.01g, 27mmol) in dichloromethane under ice-cooling; after the addition is complete, react under ice-cooling 30min. with saturated NaHCO 3 Quench the reaction with solution, extract the organic phase, anhydrous MgSO 4 After drying, the solvent was evaporated under reduced pressure to obtain p-chlorophenyl isocyanate. Dissolve L-glutamic acid (11.77g, 80mmol) with 2M NaOH (150mL) solution, dissolve the newly prepared chlorophenylisocyanate with toluene, then slowly drop it into the glutamic acid solution under ice-bath conditions, and Reaction 6h. Separate the aqueous phase, adjust the pH to 2 with 6M hydrochloric acid, then extract three times with ethyl acetate, combine the organic phases, anhydrous MgSO 4 Drying, column chromatography gave white solid 14.48g, yield 68%, ...

Embodiment 2

[0149] Example 2. 3-(1-(4-chlorophenyl)-3-(4-methylbenzyl)-2,5-dioximidazolin-4-yl)-N-hydroxypropionamide (38)

[0150] The preparation method of intermediate and target object is as embodiment 1, yield: 58%, melting point: 135-138 ℃. 1 H NMR (400MHz, CDCl 3 )δ8.91(s,1H),8.32(s,1H),7.38(d,J=8.8Hz,2H),7.34(d,J=8.9Hz,2H),7.18(d,J=8.0Hz, 2H), 7.15(d, J=8.0Hz, 2H), 4.92(d, J=15.1Hz, 1H), 4.14(d, J=15.1Hz, 1H), 3.93(d, J=3.5Hz, 1H ),2.33(s,3H),2.32–2.24(m,1H),2.16(d,J=7.2Hz,2H),2.06(dd,J=13.4,6.3Hz,1H). 13 C NMR (151MHz, DMSO-d 6 )δ171.73, 168.28, 155.32, 137.22, 133.69, 132.77, 131.42, 129.70, 129.23, 128.90, 128.38, 58.70, 44.49, 26.72, 24.48, 21.19. HRMS (AP-ESI) m / z, Calcd for C 20 h 21 ClN 3 o 4 ,([M+H] + ):402.1215,found:402.1212.

Embodiment 3

[0151] Example 3. 3-(3-Benzyl-1-(4-chlorophenyl)-2,5-dioximidazolin-4-yl)-N-hydroxypropionamide (39)

[0152] The preparation method of intermediate and target object is as embodiment 1, yield: 83%, melting point: 75-78 ℃. 1 H NMR (400MHz, DMSO-d 6 )δ10.41(s,1H),8.75(s,1H),7.58(d,J=8.7Hz,2H),7.48(d,J=8.7Hz,2H),7.44–7.26(m,5H). ,4.75(d,J=15.8Hz,1H),4.39(d,J=15.8Hz,1H),4.20(t,J=4.1Hz,1H),2.18–1.86(m,4H). 13 C NMR (151MHz, DMSO-d 6 )δ171.75, 168.27, 155.40, 136.82, 132.78, 131.42, 129.24, 129.12, 128.92, 128.32, 128.03, 58.88, 44.78, 26.71, 24.52. HRMS (AP-ESI) m / z, Calcd for C 19 h 19 ClN 3 o 4 ,([M+H] + ):388.1059,found:388.1058.

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Abstract

The invention relates to a hydantoin hydroxamic acid type selective inhibitor for a histone deacetylase 6 subtype and a preparation method and applications thereof. The selective inhibitor has a structure represented by the formula (I). The selective inhibitor has good activities on inhibiting the activity of histone deacetylase and preventing the proliferation of tumor cells and can be used to prepare drugs for treating or preventing diseases of mammals caused by abnormal expression of histone deacetylase. The invention further relates to a pharmaceutical application of a composition that contains the inhibitor represented by the formula (I).

Description

technical field [0001] The invention relates to a hydantoin hydroxamic acid histone deacetylase 6 subtype selective inhibitor, a preparation method, a pharmaceutical composition and a medical application, belonging to the technical field of medicine. Background technique [0002] Histone deacetylases (Histone deacetylases, HDACs) and histone acetyltransferase (histoneacetyltransferase, HAT) jointly maintain the balance of histone and non-histone acetylation in the body, and once the acetylation level in the body is abnormal, it will lead to various diseases such as cancer. [0003] According to differences in cellular localization and homology, the 18 members of the human HDACs family can be classified into Zn 2+ Dependent Class I(HDAC1,2,3,8), Class IIa(HDAC4,5,7,9), Class IIb(HDAC6,10), Class IV(HDAC11) and NAD + Dependent Class III (SIRT1-7). [0004] In 2006, Vorinostat (SAHA) was approved by the US FDA for the treatment of cutaneous T-cell lymphoma, a major breakthro...

Claims

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Application Information

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IPC IPC(8): C07D233/76A61P35/00A61P25/00A61P29/00A61P31/12A61P3/10A61P33/06A61K31/4174A61K31/4166
CPCC07D233/76A61P35/00A61P25/00A61P29/00A61P31/12A61P3/10A61P33/06Y02A50/30
Inventor 方浩梁涛杨新颖李孝贤
Owner SHANDONG UNIV
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